Stromal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in Glioblastoma

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2022

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Abstract

Glioblastoma (GBM) is notorious for its immunosuppressive tumor microenvironment (TME). GBM is universally lethal and remains highly refractory to immunotherapy, including immune checkpoint blockade (ICB). Resistance to ICB is a central issue in GBM and is thought to be primarily driven by tumor-imposed immune dysfunction. Here, however, we identify calmodulin-dependent kinase kinase 2 (CaMKK2) as a novel driver of ICB resistance. CaMKK2 is highly expressed in myeloid cells and neurons and is associated with worsened survival in patients with GBM. Using CaMKK2-deficient preclinical murine models, we determine that host CaMKK2 expression reduces survival and promotes ICB resistance in a T cell-dependent manner. Single-cell RNA-sequencing, flow cytometric profiling, and immunofluorescence staining of immune cells in the tumor reveal that CaMKK2 expression is associated with several pro-tumor, ICB resistance-associated immune phenotypes. For instance, CaMKK2 promotes terminal exhaustion in CD8+ T cells and reduces the expansion of effector CD4+ T cells, additionally limiting their tumor penetrance and interactions with myeloid cells. CaMKK2 also maintains myeloid cells in an Apolipoprotein E+, disease-associated microglia-like phenotype, which is associated with ICB resistance. Conversely, CaMKK2 deficiency permits the programming of tumor-associated macrophages (TAMs) to a dendritic cell (DC)-like phenotype that is associated with ICB response. Finally, we determine that it is neuronal CaMKK2 expression, specifically, that is required for maintaining the ICB resistance-associated MHC-IIlow TAM phenotype. Our findings reveal CaMKK2 as a novel contributor to ICB resistance, primarily via non-hematopoietic cells, in GBM and additionally newly identify neurons as a critical driver of pro-tumor immune phenotypes within the GBM TME.

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Tomaszewski, William Henry (2022). Stromal CaMKK2 promotes immunosuppression and checkpoint blockade resistance in Glioblastoma. Dissertation, Duke University. Retrieved from https://hdl.handle.net/10161/25849.

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